A 40-year-old female presented with rapid-onset generalized erythematous eruption with pustules agminated over the flexural areas and the flanks for 2 days. In skin histopathology, extensive subcorneal pustules, spongiosis and neutrophilic exocytosis, papillary dermal edema, and perivascular and interstitial mixed-cell infiltrates were observed. No psoriasis history but irregular intake of numerous kinds of Chinese herbal medications and the last-modified regimen including Radix Aucklandiae 14 days before the onset of pustular eruption were unveiled. Patch test showed positive result with only Radix Aucklandiae. Thus, acute generalized exanthematous pustulosis induced by Radix Aucklandiae was diagnosed.

Acute generalized exanthematous pustulosis (AGEP) is a severe cutaneous adverse reaction (SCAR), mostly induced by systemic drugs (90%), characterized by an acute-onset, sterile, pustular eruption starting from flexural areas and soon becoming generalized.[1],[2] Case reports of AGEP associated with herbal medications remain rare but have increased in the past decade. However, most of them were not confirmed by patch testing.[3],[4],[5],[6],[7],[8],[9] Herein, we report a case of AGEP induced by Radix Aucklandiae (dried root of Saussurea costus) with a definite RegiSCAR validation score and confirmed by patch testing including a series of most commonly used crude drugs in traditional Chinese medications (TCMs) in Taiwan. To our knowledge, this is the first case report of AGEP associated with Radix Aucklandiae.

Case Report

A 40-year-old female with a history of allergic rhinitis and dysmenorrhea presented to us with a rapid-onset, symmetrical, erythematous, pustular eruption on the trunk and limbs for 2 days. The eruption initially presented with erythematous patches on the back on the 1st day but soon extended to the limbs and became generalized. Numerous tiny nonfollicular pustules developed over the erythematous skin from the 2nd day of the eruption, with a predilection over the flexural areas such as bilateral axillae, scapular areas, antecubital fossae, bilateral flanks, and inner thighs [Figure 1]a, [Figure 1]b, [Figure 1]c. She had no history of previous adverse drug reactions or psoriasis. She also denied any associated viral infection symptoms or signs before the skin eruption. However, she had been taking Chinese herbal medications irregularly in the past 2 years. The latest regimen of her TCM included “magnolia flower and gypsum combination” (Xin Yi Qing Fei Tang; containing Flos Magnoliae, Radix Scutellariae, Fructus Gardeniae, Radix Ophiopogonis, Bulbus Lilii, Gypsum Fibrosum, Rhizoma Anemarrhenae, Radix Glycyrrhizae, Eriobotryae Folium, and Cimicifugae Rhizoma) and “ginseng and ginger combination” (Li Zhong Tang; containing Radix Ginseng, Rhizoma Atractylodis Macrocephalae, Zingiberis Rhizoma, and Radix Glycyrrhizae Preparata), which had been prescribed 3 weeks before the onset of the eruption. Two weeks before the onset of the skin eruption, she started a new regimen consisting of Jian Pi Wan (containing Radix Aucklandiae, Rhizoma Coptidis, Rhizoma Atractylodis Macrocephalae, Radix Glycyrrhizae, Poria, Radix Ginsen g, Massa fermentata medicinalis, Pericarpium Citri Reticulatae, Fructus Amomi, Fructus Hordei germinatus, Fructus Crataegi, Rhizoma Dioscoreae, and Semen Myristicae) and “mulberry leaf and Chrysanthemum decoction” (Sang Ju Yin; containing Folium Mori Albae, Flos Chrysanthemi, Semen Armeniacae Amarum, Fructus Forsythiae, Herba Ephedrae, Radix Platycodi, Radix Glycyrrhizae, Rhizoma Phragmitis, Herba Schizonepetae, Radix Bupleuri, and Radix Saposhnikoviae). Furthermore, she had also taken amoxicillin and acetaminophen for a 2-day duration, discontinued 6 days before the eruption. Skin biopsy from the pustular lesion on the left arm showed extensive subcorneal pustules, spongiosis and neutrophilic exocytosis in the epidermis, papillary dermal edema, perivascular and interstitial infiltration of lymphocytes, many neutrophils, and scattered eosinophils in the dermis [Figure 1]d. Blood test revealed leukocytosis (10.51 k/μL) with neutrophil count 7115/μL and no systemic organ involvement. The typical morphology and distribution, clinical course, and skin pathology fulfilled the diagnosis of AGEP with a total RegiSCAR validation score of 8 (definite case). All lesions subsided with some typical postpusular pinpoint desquamation within 12 days. Patch tests were performed 4 weeks after complete remission of the symptoms, including a screening series of 27 most commonly used crude drugs in TCM (Flos Caryophylli, Radix Angelicae Pubescentis, Cortex Cinnamomi, Cortex Radix Acanthopanacis, Caulis Impatientis, Resina Draconis/Sanguis Draconis, Fructus Cnidii, Radix Gentianae Macrophyllae, Rhizoma Ligustici Chuanxiong, Radix Aucklandiae, Flos Carthami Tinctorii, Pyritum, Radix Angelicae Sinensis, Cornu Cervi Pantotrichum, Radix Aconiti Lateralis Praeparata, Rhizoma Acori Tatarinowii, Myrrha, Rhizoma Dioscoreae Septemlobae, Rhizoma Arisaematis, Herba Lycopodii, Radix Cyathulae Officinalis, Rhizoma Pinelliae, Radix Angelicae Dahuricae, Herba Dendrobii, Secretio Moschus, Plumbi Oxidum Rubrum, and Stigmata Croci), acetaminophen, amoxicillin trihydrate, mercury, and mercury (II) amidochloride (ammoniated mercury). The screening series of 27 most commonly used crude drugs in TCM were patch tested as 10% ethanol extracts, while acetaminophen and amoxicillin trihydrate were patch tested as 10% in petrolatum and mercury and ammoniated mercury as 0.5% and 1.0% in petrolatum, respectively (Chemotechnique Diagnostics, Vellinge, Sweden). The patient was patch tested on the back using IQ Chamber® (from Chemotechnique Diagnostics AB, Vellinge, Sweden) and secured with 3M tape. The patch test material was removed after 48 h. Reading of the test was performed 72 h after the test application. The results showed only a positive reaction (+ according to the International Contact Dermatitis Research Group scoring recommendations) to Radix Aucklandiae and the other tested allergens were all negative.

Figure 1: Skin lesions 2 days after the onset of the eruption. (a) Hundreds of tiny nonfollicular pustules on an erythematous base on the lower back and bilateral flanks. (b) A closer view of the pustules on the left flank. (c) Pustules on an erythematous base on the right axilla. (d) Subcorneal pustules, spongiosis, neutrophilic exocytosis, papillary dermal edema, perivascular and interstitial infiltrates containing lymphocytes, numerous neutrophils, and scattered eosinophils are noted

AGEP is a rare, sterile inflammation of the skin, frequently associated with fever, massive neutrophilia, and mostly induced by systemic drugs (90% of the cases), especially antimicrobial agents, or sometimes by acute viral infections.[1],[2] AGEP is clinically characterized by an acute onset of nonfollicular sterile pustules on an edematous erythema, beginning from the face or intertriginous areas, quickly expanding to the trunk and limbs within a few hours, and spontaneously resolved on drug withdrawal within 2 weeks.[2] Histopathological features of AGEP include spongiform subcorneal and/or intraepidermal pustules, papillary edema, polymorphous perivascular infiltrates with neutrophils, and occasionally leukocytoclastic vasculitis, but without psoriatic acanthosis or papillomatosis.[1] Cases of AGEP in Taiwan have been shown with a higher female predominance (68.7%), high level of C-reactive protein level, normal eosinophil count in most patients, and a relatively low association with systemic drugs (62.5%), with older patients showing a stronger etiologic association with a previous sensitization by culprit drugs such as antibiotics.[10]

There is a considerable popularity of using ethnic herbal medications in Asian populations, especially the use of TCM in Taiwan. Herbal medications can cause various adverse reactions in the dermatologic field, including allergic skin reactions, photosensitization, pellagra, arsenic dermatoses, mercury poisoning, and angioneurotic edema.[11] SCARs associated with herbal medications, such as Stevens–Johnson syndrome (SJS), drug hypersensitivity syndrome, and AGEP have also been occasionally documented.[3],[11],[12]

In the past decade, the association of AGEP with different kinds of herbal medications has been increasingly identified, mostly in Asian countries. These are mainly single case reports from other countries [Table 1].[3],[4],[5],[6],[7],[8],[9] The culprit herbal agents included Gingko biloba,[4] velvet antler,[7] oral essential oil of Pistacia lentiscus,[8] and Pantax notoginseng saponins injection,[9] while other culprits were not identified [cases 1, 3, 4, 5, 6, and 7 in [Table 1]. The onset of AGEP after drug exposure usually occurs within 48 h but varies between different medications, with an even shorter latent period (median treatment duration: 1 day) for antibiotics including sulfonamides, while a longer median onset time (11 days) was found with other associated drugs.[13] Similarly, the time period from the intake of associated herbal medications to the onset of AGEP also ranges from 1 day to 1 week in the previous reports.[3],[4],[5],[6],[7],[8],[9] The currently reported case showed a slightly longer latent period of 2 weeks, but it is still reasonable. Theoretically, it usually takes longer time (7–21 days) to be sensitized when the participants do not have previous exposure to the allergens; if the participants have been sensitized to a certain allergen, it usually takes 1–2 days to elicit the allergic reactions. All the AGEP cases induced by herbal medications in the literature and in our case showed compatible histopathological features, benign clinical course, and if recorded definite RegiSCAR validation scores.

The usefulness and sensitivity of drug patch tests vary with the types of drug eruptions (more sensitive in AGEP, systemic contact dermatitis, fixed drug eruption, lichenoid, and maculopapular eruption) and also depend on the culprit drugs in each type of eruption (higher positive rates in patients patch tested with diltiazem, abacavir, β-lactam antibiotics, anticonvulsants, tetrazepam, and pseudoephedrine).[14],[15] The proportion of relevant positive patch tests has been shown significantly higher in AGEP (50%) than in other SCARs (26%), such as SJS or toxic epidermal necrolysis (TEN) (9%).[16] However, a more recent study to determine the value of drug patch test for the three main classes of SCARs showed a lower positivity rate in AGEP (58%) than in drug rash with eosinophilia and systemic symptoms (64%) but still higher than in SJS/TEN (24%).[17] Thus, patch test has become widely recognized as of value in the diagnosis of AGEP, narrowing differential diagnosis of ambiguous cases, and help in the identification of culprit agent.[1],[2] However, drug patch test has been rarely performed in the diagnosis of herbal medication-induced AGEP (except for a case induced by velvet antler)[7] nor has its relevant sensitivity been analyzed.

S. costus is a medicinal plant commonly used in the indigenous medical system in India, Tibet, Korea, and China.[18] In TCM, Radix Aucklandiae is derived from the dried root of S. costus and has the Chinese name Yun Mu Xiang.[19] Its several bioactive components have been observed as having anti-inflammatory, anticancer, hepatoprotective, antiulcer, cholagogic, immunomodulating, antimicrobial effects through different mechanisms (including the inhibitory effect on tumor necrosis factor-α and interferon-γ-induced chemokine production, inhibition on NF-kappa B pathway, and the anticomplementary activity).[18],[20],[21] Thus, S. costus has been commonly used in treating inflammation of the lungs (including chronic bronchitis and asthma), ulcer, abdominal pain, anorexia, nausea, rheumatism, and other conditions.[18],[21] Extracts of S. costus have also been reported to alleviate inflammatory chemokine production in vitro in human keratinocyte HaCaT cells and in vivo in-house dust mite-induced atopic-like dermatitis mouse model.[22] Despite several studies showing the anti-allergic effect of S. costus,[21],[22] it is also a well-known contact allergen with related haptens such as sesquiterpene lactones (including costunolide and dehydrocostuslactone),[19],[23] which have been paradoxically reported to inhibit antigen-induced degranulation with different potency in both in vivo and in vitro experiments of the asthma animal model.[21] In patients diagnosed as having allergic contact dermatitis (ACD) from TCM, Radix Aucklandiae yielded four positive reactions in 27 patients.[19] Sesquiterpene lactones (component of Radix Aucklandiae) was also suggested, along with colophonium and other nine Chinese medicinal crude drugs (Flos Caryophylli, Radix Angelicae Pubescentis, Cortex Cinnamomi, Cortex Radix Acanthopanacis, Caulis Impatientis, Resina Draconis/Sanguis Draconis, Fructus Cnidii, Radix Gentianae Macrophyllae, and Rhizoma Ligustici Chuanxiong), to be used as a screening patch test series in highly suspected cases of ACD from TCM.[19] However, the active causative ingredient of orally taken Radix Aucklandiae and its underlying mechanism involved in inducing AGEP remain unknown. The possible effects of other unknown adulterants in the TCM are also possible, giving the prevalence of adulteration as 23.7% in one Taiwanese study involving TCM associated with adverse effects and poisoning.[23] Mercury exposure has been reported as a culprit of AGEP.[24],[25] To exclude the possible adulteration of mercury in TCM leading to the development of AGEP, we performed patch testing with mercury and ammoniated mercury, and both were negative.

Conclusion

TCM as one of the culprits of AGEP should not be overlooked. A detailed investigation of herbal drug history is necessary. Patch testing can be helpful in identifying culprits of AGEP such as Radix Aucklandiae in our case.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.